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WELCOME TO THE 2011 - Harvard Initiative for Global Health ...

WELCOME TO THE 2011 - Harvard Initiative for Global Health ...

POSTER ABSTRACTS 1)

POSTER ABSTRACTS 1) Characterization of B cell responses in latent tuberculosis infection Sina Helbig, MD 1 , Sergey Rekhtmann 2 , Natasha S. Hochberg, MD, MPH 1,2 , Lisa Ganley-Leal, PhD 1 1 Section of Infectious Diseases, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA; 2 Department of Epidemiology, Boston University School of Public Health, Boston, MA 02118, USA Introduction: The role of B cell-mediated immunity in latent tuberculosis (LTBI) is poorly described. Understanding how B cells play a role in immunity to TB will help us design better therapeutics and diagnostics. Methods: We performed a case-control study in three nursing homes and enrolled 21 subjects. Tuberculosis skin test (TST) size and B cell response were evaluated in TST+ cases (n=11; prior TST positive) and TST-negative subjects (n=10; not prior TST positive). Peripheral blood mononuclear cells (PBMC) were stimulated with TB whole cell lysate (WCL) for three days and we performed flow cytometry to quantify CD69 (activation), CD27 (memory), CD77 (germinal center), Toll-like receptor (TLR)2 and TLR4 on CD19+ cells. The relationship between B cell responses and diagnostic and clinical markers was assessed. Results: We found that in TST-positive subjects CD27 and TLR4 B cell responses to WCL was significantly increased compared to cells from TST-negative subjects. In contrast, CD69 and CD77 responses did not differ between the two groups. Increases in CD27+ B cells correlated with B cell differentiation potential as measured by CD77 levels in response to WCL in TSTpositive subjects, but not TST-negative. Upregulation of TLR2 on B cells in response to WCL correlated with TST intensity suggesting a role for B cells in this diagnostic measure. Interestingly, B cell responses also negatively correlated with age among TST+ cases suggesting senescence plays a role in TB B cell immunity. Conclusion: B cell responses to TB antigens in LTBI may be robust in elderly patients. These results have implications for vaccination strategies and diagnostic evaluation in elderly patients. This work has been supported by the Section of Infectious Diseases, Boston University School of Medicine (SH) and a BIRCWH award (NH). 2) A Live/Dead reporter for Mycobacterium tuberculosis Iris Keren, Amanda Martinot, Tracy Rosebrock, Eric Rubin, Sarah Fortune and Kim Lewis. Despite having effective drugs against M. tuberculosis (MTb) for more than 60 years the disease remains a major public health problem around the world. One of the hurdles in MTb research is its long generation time, around 22 hours. We have developed a reporter for rapid identification of live and dead bacilli. The reporter is based on a plasmid that constitutively expresses mCherry and conditionally expresses GFP when an inducer is added to the medium. All cells carrying the plasmid are red while only live cells become green after addition of the inducer. Fluorescence can be analyzed by microscopy or FACS. This Live/Dead reporter is functional in vitro, in macrophages and in mice. Fluorescent bacilli were isolated from infected macrophages and analyzed over time using a FACSAria II cell sorter. We were able to observe the fluorescence bacilli (both red and green) in mouse lung tissues. The Live/Dead reporter we developed allows rapid distinction between live and dead bacilli in vitro and in vivo. These properties will make it a useful tool for both basic research and drug discovery. 15

3) Epidemiologic characteristics of IRIS-TB in a Haitian hospital Nadege Labady 1 , Mentor Ali Ber Lucien 1 1 Department of Infectiology, Universite Notre-Dame d’Haiti, Port-au-Prince, Haiti. Background: The purpose of this study is to compare the clinical characteristics of patients that developed an Immune Reconstitution Inflammatory Syndrome (IRIS) with or without tuberculosis(TB). Methodology: We conducted a retrospective cohort study at the HIV clinic at Bernard Mevs hospital (HBM), located in Port-au-Prince, Haiti. The study period was from September 2006 to August 2007. To be part of the study the criteria were: being a patient at HBM, over 18 years of age, HIV positive, Naïve ARV patients. Results: 180 (81 male and 99 female) patients from 31-50 years old were part of the study. 54 patients or 30% (26 male and 28 female) developed IRIS. 7 male and 7 seven women had IRIS/TB. For those of IRIS without TB: 19 male and 21 female. The mean–time before presence of TB in IRIS patients is 8 weeks while this for apparition of IRIS in the population without TB is 14 weeks. Out of those 54 patients, 9 (64%) developed extra pulmonary TB and only 5 (36%) are pulmonary. The mortality rate of IRIS/TB is 21 %, whereas IRIS without TB it is 45%. Furthermore CD4 count for IRIS/TB patients was less than 100 cell/mm 3 for 50% of patients and between 100 and 200 cell/mm 3 for the other 50%. For IRIS patients without TB 45% had a CD4 100. Conclusions: TB is more often extra pulmonary in IRIS patients. TB is also a minor contributor of mortality among IRIS patients. 4) CD1a dextramers detect human lipopeptide-specific T cells Anne G Kasmar 1 , Kelly G Magalhaes 1 , David C Young 1 , Tan-Yun Cheng 1 , Marie Turner 2 , Andre Schiefner 3 , Ravi Kalathur 4 , Ian A Wilson 4 , John Shires 5 , John Altman 5 , Søren Jakobsen 6 and DB Moody 1 1 Division of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115; 2 Tuberculosis Treatment Unit, Lemuel Shattuck Hospital, Jamaica Plain, MA 02130; 3 Technische Universität München; 4 Department of Molecular Biology and Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037; 5 Emory Vaccine Center, Atlanta, GA 30329; 6 Immudex, Copenhagen, Denmark αβ T cells were previously thought to solely recognize peptides. Studies over the last decade show that CD1 molecules present lipid, glycolipid, and lipopeptide antigens to T cells. Investigation of CD1 function during infection in vivo has been dominated by the study of one major population, CD1d-restricted Natural Killer T (NKT) cells; however, NKT cells are only one part of the larger family of CD1-restricted T cells. Study of the natural immunological functions of these cells has been hampered by lack of molecular reagents that can identify fresh polyclonal T cells directly ex vivo. In vitro study of CD1a-restricted T cell clones demonstrates proliferation, cytolysis and release of cytokines in response to lipid ligands presented by CD1a. These studies raise the possibility that CD1a-restricted T cells play a role in natural immunity to infection. Because CD1a presents the mycobacterial pre-siderophore dideoxymycobactin (DDM) to human T cells in vitro, we hypothesized that lipid-loaded CD1a dextramers could detect DDMspecific T cells during natural infection. We developed dideoxymycobactin-loaded CD1a dextramers and found that they specifically stain CD1a-restricted T cell lines. Staining was dependent on the stereochemistry of the lipid antigen and was blocked by pre-incubation with either anti-CD1a antibody or soluble T cell receptors. Further, DDM-loaded dextramers failed to 16

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